The alarming rise in the frequency of diabetes and obesity in worldwide populations has prompted major changes in public policy as well as a shift in biomedical research toward improving our understanding of how misregulation of metabolism can lead to disease. Central to this epidemic of metabolic disorders is the striking correlation between the metabolic health of the parents and that of their offspring. There is a vast literature describing this phenomenon in rats and mice, demonstrating that temporary nutritional changes in the parental generation can have major effects on the metabolic status of their adult offspring maintained on a normal diet. This includes an increased risk for developing type 2 diabetes and obesity. Epidemiological studies of adults born during the Dutch Hunger Winter of 1944, along with other more correlative studies, have demonstrated that similar inherited effects on metabolism can be seen in humans. Molecular studies have shown that changes in epigenetic chromatin marks in offspring are associated with changes in parental diet, providing a potential molecular mechanism to explain the inherited effects on metabolism. In spite of these extensive studies, however, the research in this area remains correlative. Only a few genetic approaches have been used to characterize the inheritance of metabolic state, and there is no defined molecular mechanism to explain this association. We have discovered that the fruit fly Drosophila shares the ability to link the metabolic status of parents with that of their offspring, that transmission can be seen through both the male and female germline, that metabolic dysfunction carries through to the F2 and F3 generations, and that the phenotypes are similar to those reported in rodent and human studies. We have identified a nuclear receptor that contributes to this response, DHR96, and have shown that genetic changes in epigenetic state can lead to metabolic dysfunction in the offspring. We propose here two specific aims to extend these initial observations. First, we will define the physiological and metabolic defects seen in the adult offspring of parents subjected to different transient dietary treatments. These experiments will include metabolomic profiling, transcriptional profiling by RNA-seq, tissue-specific and sex-specific genetic studies, and testing different dietary treatments. Second, we will characterize the epigenetic regulation of transgenerational metabolic control by determining the genome- wide changes in key histone modifications in the parental germline and mature adult offspring of wild-type parents subjected to different diets. We will also perform focused genetic studies to test specific models for metabolic dysfunction that arise from this work. Our goal in this research is to exploit the genetic strengths of Drosophila for studies of metabolic regulation and epigenetic control, providing, for the first time, a simple model system to define the molecular mechanisms that control transgenerational metabolic inheritance.